Therapeutic system comprising amoxicillin and clavulanic acid

ABSTRACT

The present invention relates to a novel therapeutic system suitable for one or twice daily administration of amoxicillin and clavulanic acid. One part of the dosage is provided by at least one immediate release amoxicillin/clavulanic acid pharmaceutical composition, and the other part of the dosage is provided by at least one delayed and sustained release gastroretentive amoxicillin pharmaceutical composition.

The present invention belongs to the field of pharmaceutical technologyand relates to a novel therapeutic system suitable for once ortwice-daily administration of amoxicillin and clavulanic acid. Thetherapeutic system comprises at least one immediate releaseamoxicillin/clavulanic acid composition and at least one gastroretentivepharmaceutical composition with delayed and sustained release ofamoxicillin.

There is a constant need for new patient-friendly medicaments andpharmaceutical compositions which comprise amoxicillin and clavulanicacid and provide a simple and reliable method of administration and moreeffective treatment of bacterial infections.

Various pharmaceutical compositions comprising amoxicillin (present astrihydrate) and clavulanic acid (present as potassium clavulanate) areprovided. In available compositions amoxicillin and clavulanic acid arein the ratio 2:1, 4:1, 7:1, 8:1, 14:1 and 16:1. They are intended forthree- or two-times daily administration. In most examples the releaseof active ingredients from the pharmaceutical composition startsimmediately after the composition reaches the stomach.

It is known that amoxicillin substance has the absorption window in theupper gastrointestinal tract, that is, in the stomach and in the uppersmall intestine.

EP 1044680 describes modified release pharmaceutical formulationscomprising 1900 to 2600 mg of amoxicillin and such an amount ofclavulanic acid to provide a ratio of amoxicillin to clavulanate in therange 12:1 to 20:1. They are formulated from the phase providingimmediate release of clavulanic acid and a part of amoxicillin and thephase providing slow release of amoxicillin. Preferably they aremultilayer tablets. The formulations described are suitable for twicedaily administration.

WO 02/30392 describes formulations which allow for once daily dosingregimen of amoxicillin and clavulanic acid and provide amoxicillinconcentrations greater than MIC=2 μg/ml for at least 8 hours of thedosing interval. They are suitable only for the treatment of mildinfections. The single daily dose is 1700 to 2500 mg of amoxicillin and100 to 150 mg of potassium clavulanate. The daily dose may be providedby one tablet, e.g. dispersible or chewing tablet, or severalconventional tablets or capsules may be combined, of which somecomprising amoxicillin and clavulanate, others only amoxicillin. Thetablet containing two types of granulates is described. The immediaterelease granulate comprising amoxicillin trihydrate and the slow releasegranulate comprising crystalline sodium amoxicillin, citric acid xanthangum and other excipients. In the stomach, this tablet disintegrates toits basic granules wherein immediate release granules are dissolvedimmediately and amoxicillin is absorbed. Slow-release granules aredissolved slowly, probably a part of the granules leaving the stomachbefore being dissolved. If undissolved granules pass the upper smallintestine, where the amoxicillin absorption window is, that part ofamoxicillin is not absorbed at all. Such formulation is not suitable forthe treatment of infections caused by more resistant strains.

Modified release pharmaceutical formulations comprising amoxicillin andclavulanic acid are also known from the patent applications WO 95/20946,WO 95/28148, WO 96/04908, WO 94/27557 and WO 98/22091.

DESCRIPTION OF THE INVENTION

The present invention relates to a therapeutic system suitable for onceor twice-daily administration of amoxicillin and clavulanic acid. Onepart of the dosage is provided by at least one immediate releaseamoxicillin/clavulanic acid pharmaceutical composition and the otherpart of the dosage is provided by at least one gastroretentivepharmaceutical composition with delayed and sustained release ofamoxicillin.

The essence of the invention is the use of the pharmaceuticalcomposition which is retained in the stomach and provides delayed andsustained release of amoxicillin in the stomach. Dissolved amoxicillinis absorbed from the stomach or enters the upper segment of the smallintestine where it is immediately and rapidly absorbed. This way theoptimal absorption of amoxicillin is achieved because practically allamoxicillin is absorbed before passing the amoxicillin absorptionwindow. Thus, in comparison with the pharmaceutical formulations whichdo not provide retention in the stomach, higher bioavailability andsuitable amoxicillin plasma concentrations may be achieved with evenlower dosages for once or twice-daily administration. In comparison withexisting formulations, the suitable therapeutic amoxicillin plasmaconcentrations are achieved with the lower amoxicillin dose within adaily dosing interval.

This way, amoxicillin plasma concentrations are maintained which onaverage do not differ much from the C_(max) (maximum amoxicillinconcentration in the blood) that would occur after administration of theimmediate release dosage only which is the part of described therapeuticsystem. Thus, the amoxicillin concentrations in the gastrointestinaltract are in the range where no absorption saturability occurs. Thisway, no active substance is lost due to the absorption window andconsequently with the less unabsorbed active substance fewergastrointestinal adverse effects might be expected in respect to higherdosages which pass the absorption window.

The novel therapeutic system is more patient-friendly and isadvantageous over the known pharmaceutical formulations intended fortwo- or three-times daily oral administration of amoxicillin andclavulanic acid. Said therapeutic system provides the simple andreliable posology and administration of the drug as directed by thephysician and recommended by the manufacturer. This way the moreeffective treatment is provided.

The therapeutic system of the present invention is intended for theempiric treatment of mild to moderate bacterial infections caused by thebacterial strains susceptible to the combination of amoxicillin andclavulanic acid. Bacterial strains among others include gram-positiveaerobic bacteria, such as St. pneumoniae, St. pyogenes, St. viridans,St. bovis, Staph. aureus, Staph. epidermidis, Listeria spp.,Enterococcus spp., gram-negative aerobic bacteria, such as H.influenzae, M. cattharalis, E. coli, Proteus spp., Klebsiella spp., N.gonorrhoeae, N. meningitidis, Pasteurella multocida and anaerobicbacteria, such as Peptococcus spp., Peptostreptococcus spp., Clostridiumspp., Actinomyces israellii.

If the therapeutic system of the invention is administered twice dailyit may be used also for the empiric treatment of infections caused bybacterial strains with reduced susceptibility to amoxicillin alone, suchas St. pneumoniae, and for the treatment of infections caused bybacterial strains susceptible to the combination of amoxicillin andclavulanic acid.

The bacteria mentioned above cause upper and lower respiratory tractinfections, urinary tract infections, genital tract infections,gonorrhoea, skin and soft tissue infections, bone and connective tissueinfections, cholecystitis, periodontal tissue infections, infectionsassociated with animal or human bites, and mixed infections caused bygram-negative and gram-positive microorganisms and aerobes: chronicsinusitis and otitis media, peritonsillar abscess, breast abscess,aspiration pneumonia, peritonitis, cholangitis, postoperativeintraabdominal complications, abdominal infections.

Pharmacokinetic properties of the therapeutic system of the presentinvention provide concentrations of amoxicillin and clavulanic acid inthe plasma and consequently in the tissues which are therapeuticallyeffective and reach or exceed minimum inhibitory concentration (MIC) ofa presumed causative organism for the amoxicillin/clavulanic acidcombination. The minimum inhibitory concentration (MIC) is theconcentration of amoxicillin and clavulanic acid still inhibitingmultiplication of the respective bacterial strain. For most isolatedclinical strains the minimal inhibitory concentration for theamoxicillin/clavulanic acid combination is 1.0/0.5 μg/mL or less usingthe standard method for the MIC determination in the ratio amoxicillinto clavulanic acid 2:1. For bacterial strains with reducedsusceptibility to amoxicillin/clavulanic acid combination the minimalinhibitory concentration is 4.0/2.0 μg/mL or less using the standardmethod for the MIC determination in the ratio amoxicillin to clavulanicacid 2:1.

The therapeutic system of the present invention administered once dailymay provide the amoxicillin concentrations of 4.0 μg/mL at least for 7hours within the 24 hours dosing interval. It is similar to the existingpharmaceutical amoxicillin/clavulanic acid formulations for twice orthree-times daily oral administration.

The therapeutic system of the present invention administered once dailycan be used for the treatment of the infections due to confirmed orsuspected β-lactamase-producing pathogens susceptible toamoxicillin/clavulanic acid combination.

The therapeutic system of the present invention administered twice dailymay provide the amoxicillin concentrations of 8.0 μg/mL at least for 3.5hours within the 12 hours dosing interval. The plasma concentrations ofamoxicillin achieved are above the MIC for a longer period of time thanthose achieved with conventional pharmaceutical formulations for twicedaily administration.

The therapeutic system administered twice daily may be applicable in thecase of infections due to confirmed or suspected β-lactamase-producingpathogens with reduced susceptibility to amoxicillin alone, for examplein the case of St pneumoniae where the resistance mechanism is notβ-lactamase-mediated. The suitable single dose for twice dailyadministration may be, for instance, about 1600 mg of amoxicillin andabout 125 mg of clavulanic acid. Said dosage regimen is suitable inpreventing the development of the resistance of bacteria (at least 30%of the dosing interval is above MIC=8 μg/mL, at least 40% of the dosinginterval is above MIC=4 μg/mL and at least 60% of the dosing interval isabove MIC=1 μg/mL or at least 60% of the dosing interval is above MIC=4μg/mL, at least 80% of the dosing interval is above MIC=2 μg/mL and atleast 90% of the dosing interval is above MIC=1 μg/mL). Said formulationis closer to the infusion which is clinically from theoretical point ofview a perfect posology approach for administration of β-lactamantibiotics in comparison to administration in intervals. Said mode ofadministration of the novel formulation twice daily is suitable forinitiation of the treatment, also known as a loading dose in the medicalterminology which enables to achieve rapidly the effective concentrationof the antimicrobial medicament in the blood.

A single dose of amoxicillin/clavulanic, which is administered once ortwice daily is provided by a combination of one or more pharmaceuticalcompositions wherefrom amoxicillin and clavulanic acid are releasedquickly after the ingestion, and one or more pharmaceutical compositionswhich are retained in the stomach wherefrom amoxicillin is releasedslowly to provide the concentration of amoxicillin of 4.0 μg/mL for atleast 7 hours and 1.0 μg/mL for at least 12 hours for once dailyadministration and provide the concentration of amoxicillin of 8.0 μg/mLfor at least 7 hours and 1.0 μg/mL for at least 15 hours for twice dailyadministration.

The daily dose of amoxicillin, provided by once or twice dailyadministration, may preferably be from about 800 to about 6000 mg, andthe dose of clavulanic acid from about 50 to about 375 mg. Amoxicillinand clavulanic acid may be in the ratio from 3:1 to 35:1. Preferred arethe compositions comprising amoxicillin and clavulanic acid in the ratio10:1 to 30:1, and most preferred in the ratio 12:1, 13:1, 22:1.

Amoxicillin may be in the form of amoxicillin trihydrate or crystallinesodium amoxicillin or as the combination thereof. Clavulanic acid may bein the form of a salt, such as potassium clavulanate.

Preferred single doses may be 1500/125, 1600/125, 2000/125, 2750/125 and2650/80.

One or more pharmaceutical compositions providing the part of the dosefor immediate release may contain from about 300 to about 2000 mg ofamoxicillin and from about 50 to about 250 mg of clavulanic acid.

The part of the dose for immediate release may be provided by one ormore immediate release pharmaceutical compositions selected from thegroup comprising a tablet, film coated tablet, rapidly disintegratingtablet, dispersible tablet, effervescent tablet, chewing tablet,capsule, single dose sachet comprising granulate, suspension andpellets. It is possible to combine more compositions which may be thesame or different, of the same or different dosage. For example, one ormore tablets 500/125, 875/125, 500/62.5, 1000/80, 1000/125, 1050/125 mg,a dispersible tablet 500/125, 875/125 1000/125, 1000/80, 1050/125 mg maybe used, or the combinations thereof. Some tablets may compriseamoxicillin and clavulanic acid, others amoxicillin only. The use of oneimmediate release amoxicillin/clavulanic acid pharmaceutical combinationis preferred.

The immediate release amoxicillin/clavulanic acid pharmaceuticalcomposition may also comprise absorption enhancers which improveamoxicillin absorption from the gastrointestinal tract. Suitableabsorption enhancers may be surface active agents, fatty acids,middle-chain glycerides, steroid detergents (bile acid salts), acylcarnitine and alkanoyl cholines (carnitine and choline esters withmiddle- and long-chain fatty acid), N-acyl derivatives of α-amino acids,N-acyl derivatives of non-α-amino acids, chitosans and othermucoadhesive polymers. Especially suitable absorption enhances may be,for instance, sodium deoxycholate, sodium taurocholate, polysorbate 80,sodium lauryl sulfate, sodium dodecylsulfate, octanoic acid, sodiumdocusate, sodium laurate, glyceryl monolaurate, stearic acid, palmiticacid, palmitoleic acid, glyceryl monooleate, ethylenediaminotetraaceticacid, sodium edetate, sodium citrate, β-cyclodextrine and sodiumsalicylate. Preferred absorption enhancers are sodium deoxycholate,sodium docusate and sodium lauryl sulfate.

The part of the dose for delayed and sustained release of amoxicillin isprovided by one or more pharmaceutical gastroretentive compositionswhich are retained in the stomach. Suitable gastroretentivepharmaceutical compositions may be, for instance, floatingpharmaceutical compositions, heavy pharmaceutical compositions,bioadhesive pharmaceutical compositions, expandable pharmaceuticalcompositions, pharmaceutical compositions which retain in the stomachdue to their specific form and cannot pass through the pylorus into theduodenum and the like. Suitable floating pharmaceutical compositions maybe, for instance, a floating capsule or a floating tablet, preferably, afloating capsule. The part of the dose for delayed and sustained releasemay be divided between more than one floating capsules or tablets. Thesaid part preferably comprises from 500 to 2000 mg of amoxicillin.Optionally, the gastroretentive pharmaceutical composition may alsocomprise clavulanic acid.

The dose of 1500 mg of amoxicillin and 125 mg of clavulanic acid may beprovided, for instance, by one film coated tablet 500/125 and twofloating capsules each comprising 500 mg of amoxicillin. The dose of1600 mg of amoxicillin and 125 mg of clavulanic acid, may be provided,for instance, by one film coated tablet 500/125 and two floatingcapsules each comprising 550 mg of amoxicillin, the dose of 2650 mg ofamoxicillin and 80 mg of clavulanic acid, for instance, by onedispersible tablet 1000/80 and three floating capsules each comprising550 mg of amoxicillin. The dose of 2525 mg of amoxicillin and 125 mg ofclavulanic acid may be provided, for instance, by one film coated tablet875/125 and three floating capsules each comprising 550 mg ofamoxicillin. The dose of 2000 mg of amoxicillin and 125 mg of clavulanicacid may be provided, for instance, by one film coated tablet 500/125and three floating capsules each comprising 500 mg of amoxicillin.

Further the dose of 1550 mg of amoxicillin and 125 mg of clavulanicacid, may be provided, for instance, by one film coated tablet 1000/125and one floating capsule comprising 550 mg of amoxicillin. The dose of1600 mg of amoxicillin and 125 mg of clavulanic acid, may be provided,for instance, by one film coated tablet 1050/125 and one floatingcapsule comprising 550 mg of amoxicillin. The dose of 2000 mg ofamoxicillin and 125 mg of clavulanic acid may be provided, for instance,by one film coated tablet 900/125 and two floating capsules eachcomprising 550 mg of amoxicillin.

The present invention also relates to a delayed and sustained releaseamoxicillin floating capsule (gastroretentive composition) used in thetherapeutic system of the present invention to provide for the dailydose in the combination with an immediate release amoxicillin/clavulanicacid pharmaceutical composition. The release of amoxicillin is delayedfor about one hour being defined by dissolving of the capsule cap or thecoating of the capsule.

The floating capsule of the invention comprises a coated capsule body,coated or uncoated capsule cap, the granulate and at least one tabletwherein the granulate and the tablet comprise amoxicillin. Amoxicillinmay be in the form of trihydrate or crystalline sodium amoxicillin orthe combination thereof. The capsule body and the cap basic material maybe a polymer material such as, e.g., hydroxypropylmethylcellulose(HPMC), gelatine and starch. Preferably, the capsule is made fromhydroxypropylmethylcellulose.

The capsules may be wholly coated, or only a capsule body may be coated.A body and a cap may be coated with the same or different coating. Ifcoatings are different, a cap coating must be dissolved prior to acapsule body coating.

Suitable coatings may be well soluble, poorly soluble, or slowlydissolving coatings. Suitable soluble or insoluble polymers, orcombinations of insoluble polymers with soluble polymers may be, e.g.,combinations of ethylcellulose and hydropropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose orpolyvinylpyrrolidone, combinations ofmethacrylate/trimethylammonioethylmethacrylate copolymers (e.g.,Eudragit RL PO, Eudragit RL 100, Eudragit RL30D, Eudragit RS PO,Eudragit RS 100, Eudragit RS30D or combinations thereof) andhydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose or methylcellulose, combinations of a neutralpolymer of methacrylate (e.g., Eudragit NE 30 D, Eudragit NE 40 D) andhydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose, methylcellulose or polyvinylpyrrolidone.

The coatings may further comprise other excipients conventionally usedin the coatings such as fillers, e.g., talc, lactose, polysaccharidesand the like, plasticizers, e.g., dibutyl sebacate, triethyl citrate,polyethylene glycol, adipic acid, coconut oil, oleic acid and the like,colorants, e.g., titanium dioxide, lakes, pigments and the like,antioxidants and other excipients. The coating may also comprisebioadhesive polymers.

A particularly suitable coating is the combination of ethylcellulose andhydropropylcellulose or the combination of Surelease® andhydroxypropylmethylcellulose in the ratio from 70:30, 60:40 to 50:50.Surelease® is Colorcon's trade mark for the aqueous dispersion ofethylcellulose.

Prior to application of the functional coating, the capsule or capsuleparts may be coated with a dispersion (solution or suspension) of ahydrophilic polymer, e.g., hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose.

The capsules or their parts may be coated empty (before filling) or thecapsules already filled with the granulate and tablets are coated. Theamount of the coating to be used may be from 0.5 to 10 mg/cm² if coatedprior to filling or from 0.5 to 30 mg/cm² if the capsules already filledwith granulate and tablets are coated. The suitable coat thickness maybe from 2 to 200 μm, preferably 10 to 50 μm if coated before filling and2 to 600 μm if the capsules already filled with granulate and tabletsare coated, respectively.

Sustained release may be achieved with the type of the coating or acombination of the coated body and uncoated cap or a combination ofdifferent coatings.

The coatings may be applied by the techniques which are conventional forcapsule or tablet coating in pharmaceutical technology. The coatingdispersion may be a solution or suspension of polymers and otherexcipients. Suitable solvents for the preparation of the coatingdispersion may be, for instance, water, ethanol, methanol, propan-2-ole,acetone, ethyl acetate, acetic acid, glycols, dichloromethane,dimethylformamide, dimethysulfoxide, chloroform, toluene, methylenechloride, benzene, ethoxyethyl acetate, ethylene glycol monoacetate,ethyl lactate, monoethyl acetate, methylethyl ketone and combinationsthereof.

The capsules or their parts, that is, the capsule body or cap, inaddition to the first functional coating, may be also coated with thesecond functional coating which by the composition may be the same ordifferent from the first coating. For the second coating, soluble orinsoluble polymers or a combination of insoluble and soluble polymersmay be used. Other excipients may be the same or different from theexcipients of the first coating. The procedures for preparing the secondfunctional coating may be the same as the procedures for preparing thefirst functional coating.

The granulate comprises amoxicillin and at least one release-controlhydrophilic or lipophilic substance. Polymer or nonpolymer substancesmay be used. Suitable polymer substances may be selected from a groupcomprising hydroxypropylcellulose, hydroxypropylmethylcellulose,methylcellulose, ethylcellulose, hydroxyethylcellulose, sodiumcarboxymethylcellulose, cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxymethylcellulose phthalate, polyvinyl alcohol,polyvinylpyrrolidone, methylhydroxyethylcellulose, polymers andcopolymers of acrylic and methylacrylic acid, copolymers ofethylacrylate and methylacrylate, maltodextrin, xanthan gum, guar gum,acacia, alginic acid and sodium alginate. Suitable nonpolymers may becarnauba wax, cetyl alcohol, hydrogenated vegetable oil, hydrogenatedcastor oil, glycerol monostearate, glycerol palmitostearate, a mixtureof mono-, di- and triglycerides and the like.

Preferably hydroxypropylmethylcellulose, methylcellulose andethylcellulose are used.

The granulate may further comprise other excipients, for instance,different fillers, binders, disintegrants, glidants, lubricants andabsorption enhancers of amoxicillin from the gastrointestinal tract.Suitable fillers may be microcrystalline cellulose, powdered cellulose,lactose, starch, pregelatinized starch, saccharose, glucose, mannitol,sorbitol, calcium phosphate, calcium hydrogen phosphate, aluminiumsilicate, sodium chloride, potassium chloride, calcium carbonate,calcium sulfate, dextrates, dextrin, maltodextrin, glycerolpalmitostearate, hydrogenated vegetable oil, kaolin, magnesiumcarbonate, magnesium oxide, polymethacrylates, talc and the like,preferably microcrystalline cellulose and lactose. Suitable binders maybe starch, pregelatinized starch, gelatine, sodiumcarboxymethylcellulose, polyvinylpyrrolidone, alginic acid, sodiumalginate, acacia, carbomer, dextrin, ethylcellulose, guar gum,hydrogenated vegetable oil, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, glucose syrup,magnesium aluminium silicate, maltodextrin, polymethacrylates, zein,preferably hydroxypropylcellulose, hydroxypropylmethylcellulose andpolyvinylpyrrolidone. Suitable disintegrants may be selected fromstarch, pregelatinized starch, sodium starch glycolate, sodiumcarboxymethylcellulose, cross-linked sodium carboxymethylcellulose,calcium carboxymethylcellulose, methylcellulose, microcrystallinecellulose, powdered cellulose, polacrilin potassium, cross-linkedpolyvinylpyrrolidone, alginic acid, sodium alginate, colloidal silicondioxide, guar gum, magnesium aluminium silicate and the like, preferablysodium starch glycolate, cross-linked sodium carboxymethylcellulose andcross-linked polyvinylpyrrolidone. Suitable glidands may be magnesiumstearate, calcium stearate, aluminium stearate, stearic acid, palmiticacid, cetanol, stearol, polyethylene glycols of different molecularweights, magnesium trisilicate, calcium phosphate, colloidal silicondioxide, talc, powdered cellulose, starch and the like, preferablycolloidal silicon dioxide. Suitable lubricants may be stearic acid,calcium magnesium, zinc or aluminium stearate, siliconized starch,glycerol monostearate, glycerol palmitostearate, hydrogenated castoroil, hydrogenated vegetable oil, mineral oil, light mineral oil,polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodiumstearyl fumarate, talc and the like. Preferred lubricants are calcium ormagnesium stearate and stearic acid.

Suitable absorption enhancers of amoxicillin may be selected fromsuitable surface active agents, fatty acids, middle-chain glycerides,steroid detergents (bile acid salts), acyl carnitine and alkanoylcholines (carnitine and choline esters with middle-and long-chain fattyacid), N-acyl derivatives of α-amino acids, N-acyl derivatives ofnon-α-amino acids, chitosans and other mucoadhesive polymers. Especiallysuitable absorption enhances may be, for instance, sodium deoxycholate,sodium taurocholate, polysorbate 80, sodium lauryl sulfate, sodiumdodecylsulfate, octanoic acid, sodium docusate, sodium laurate, glycerylmonolaurate, stearic acid, palmitic acid, palmitoleic acid, glycerylmonooleate, sodium taurocholate, ethylenediaminotetraacetic acid, sodiumedetate, sodium citrate, β-cyclodextrine and sodium salicylate.Preferred absorption enhancers are sodium deoxycholate, sodium docusateand sodium lauryl sulfate.

The granulate may be prepared by the techniques conventionally used inthe pharmaceutical art for the preparation of the granulates, forexample, simple mixing of the blend of powders (direct mix) and dry orwet granulation. For dry granulation, for instance, the slugging orcompacting procedure may be used. A suitable solvent for wet granulationmay be, for instance, water, ethanol, methanol, propan-2-ole, acetone,ethyl acetate, acetic acid, glycols, dichloromethane, dimethylformamide,dimethylsulfoxide, chloroform, toluene, methylene chloride, benzene,ethoxyethyl acetate, ethylene glycol monoacetate, ethyl lactate,monoethyl acetate, methylethyl ketone and combinations thereof.

The tablet comprises amoxicillin and excipients which are the same as inthe granulate, or may be different. The tablet composition may bequalitatively and expressed by percentage the same or different from thegranulate composition. Optionally, the tablet may be prepared only fromexcipients without amoxicillin.

The floating capsule of the present invention may include one or moretablets. By composition they may be the same or different. The tabletcomprising amoxicillin may be combined with tablets without amoxicillin,tablets with the composition being the same of different from thecomposition of the granulate.

The tablet comprises at least one release-control hydrophilic orlipophilic substance to control the release. Polymer or nonpolymersubstances may be used. Suitable polymer substances may behydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose,cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxymethylcellulose phathalate, polyvinyl alcohol,polyvinylpyrrolidone, methylhydroxyethylcellulose, polymers andcopolymers of acrylic and methylacrylic acid, copolymers ofethylacrylate and methylacrylate, maltodextrin, xanthan gum, guar gum,acacia, alginic acid and sodium alginate. Nonpolymers may be carnaubawax, cetyl alcohol, hydrogenated vegetable oil, hydrogenated castor oil,glycerol monostearate, glycerol palmitostearate, a mixture of mono-, di-and triglycerides and the like.

Preferably hydroxypropylmethylcellulose, methylcellulose andethylcellulose are used.

The tablet may also comprise other excipients, for instance, fillers,binders, disintegrants, surfactants, glidants, lubricants and absorptionenhancers of amoxicillin from the gastrointestinal tract. Suitablefillers may be microcrystalline cellulose, powdered cellulose, lactose,starch , pregelatinized starch, saccharose, glucose, mannitol, sorbitol,calcium phosphate, calcium hydrogen phosphate, aluminium silicate,sodium chloride, potassium chloride, calcium carbonate, calcium sulfate,dextrates, dextrin, maltodextrin, glycerol palmitostearate, hydrogenatedvegetable oil, kaolin, magnesium carbonate, magnesium oxide,polymethacrylates, talc and the like, preferably microcrystallinecellulose and lactose. Suitable binders may be starch, pregelatinizedstarch, gelatine, sodium carboxymethylcellulose, polyvinylpyrrolidone,alginic acid, sodium alginate, acacia, carbomer, dextrin,ethylcellulose, guar gum, hydrogenated vegetable oil, methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, glucose syrup, magnesium aluminiumsilicate, maltodextrin, polymethacrylates, zein, preferablyhydroxypropylcellulose, hydroxypropylmethylcellulose andpolyvinylpyrrolidone. Suitable disintegrants may be starch,pregelatinized starch, sodium starch glycolate, sodiumcarboxymethylcellulose, cross-linked sodium carboxymethylcellulose,calcium carboxymethylcellulose, methylcellulose, microcrystallinecellulose, powdered cellulose, polacrilin potassium, cross-linkedpolyvinylpyrrolidone, alginic acid, sodium alginate, colloidal silicondioxide, guar gum, magnesium aluminium silicate and the like, preferablysodium starch glycolate, cross-linked sodium carboxymethylcellulose andcross-linked polyvinylpyrrolidone. Suitable glidands may be magnesiumstearate, calcium stearate, aluminium stearate, stearic acid, palmiticacid, cetanol, stearol, polyethylene glycols of different molecularweights, magnesium trisilicate, calcium phosphate, colloidal silicondioxide, talc, powdered cellulose, starch and the like preferablycolloidal silicon dioxide. Suitable lubricants may be stearic acid,calcium magnesium, zinc or aluminium stearate, siliconized starch,glycerol monostearate, glycerol palmitostearate, hydrogenated castoroil, mineral oil, light mineral oil, polyethylene glycol, sodiumbenzoate, sodium lauryl sulfate, sodium stearyl fumarate, talc and thelike. Preferred lubricants are calcium or magnesium stearate and stearicacid. Suitable absorption enhancers of amoxicillin may be selected fromsuitable surfactants, fatty acids, middle-chain glycerides, steroiddetergents (bile acid salts), acyl carnitine and alkanoyl cholines(carnitine and choline esters with middle- and long-chain fatty acid),N-acyl derivatives of α-amino acids, N-acyl derivatives of non-α-aminoacids, chitosans and other mucoadhesive polymers. Especially suitableabsorption enhances are, for instance, sodium deoxycholate, sodiumtaurocholate, polysorbate 80, sodium lauryl sulfate, sodiumdodecylsulfate, octanoic acid, sodium laurate, glyceryl monolaurate,stearic acid, palmitic acid, palmitoleic acid, glyceryl monooleate,sodium taurocholate, ethylenediaminotetraacetic acid, sodium edetate,sodium citrate, β-cyclodextrine and sodium salicylate. Preferredabsorption enhancers are sodium deoxycholate, sodium docusate and sodiumlauryl sulfate. The tablets may be prepared by the techniques known inthe pharmaceutical technology, that is, by direct tabletting the blendof powders or by tabletting the granulate prepared by wet or drygranulation. For dry granulation, for instance, the slugging orcompacting procedure is used. A suitable solvent for wet granulation maybe, for instance, water, ethanol, methanol, propan-2-ole, acetone, ethylacetate, acetic acid, glycols, dichloromethane, dimethylformamide,dimethylsulfoxide, chloroform, toluene, methylene chloride, benzene,ethoxyethyl acetate, ethylene glycol monoacetate, ethyl lactate,monoethyl acetate, methylethyl ketone and combinations thereof.

Absorption enhancers of amoxicillin from the gastrointestinal tract maybe in the granulate and/or in the tablet of the floating pharmaceuticalcomposition. They may be either in the immediate release pharmaceuticalcomposition, or in the floating pharmaceutical composition or in theboth.

The present invention further relates to the method of treatment ofbacterial infections comprising once or twice daily administration of atherapeutic system comprising at least one immediate releaseamoxicillin/clavulanic acid pharmaceutical composition and at least onedelayed and sustained release amoxicillin pharmaceutical compositionwhich is retained in the stomach. Said therapeutic system provides in 24hours the amoxicillin plasma concentration of >4.0 μg/mL for at least 7hours and >1.0 μg/mL for at least 12 hours for once daily administrationand provide the concentration of amoxicillin of 8.0 μg/mL for at least 7hours and 1.0 μg/mL for at least 15 hours for twice daily administrationbeing greater than the MIC for the majority of strains which aresusceptible to the amoxicillin/clavulanic acid combination. Thetherapeutic system of the present invention administered once daily maybe used for the treatment of the infections due to confirmed orsuspected β-lactamase-producing pathogens susceptible toamoxicillin/clavulanic acid combination or may be administered twicedaily in the case of infections due to confirmed or suspectedβ-lactamase-producing pathogens with reduced susceptibility toamoxicillin alone, for example in the case of St pneumoniae where theresistance mechanism is not β-lactamase-mediated.

The invention further relates to a therapeutic system which provides thedaily dose of amoxicillin without clavulanic acid whereat the part ofthe daily dose is at least one immediate release amoxicillinpharmaceutical composition and the delayed and sustained release ofamoxicillin is provided by at least one pharmaceutical composition whichis retained in the stomach and is preferably a floating capsule.

The therapeutic system of said invention, that is, at least oneimmediate release amoxicillin/clavulanic acid pharmaceutical compositionand at least one delayed and sustained release amoxicillinpharmaceutical composition which is retained in the stomach andrepresents a single dose, is packed in a separate part of a blister.Single doses are separated by the blister perforation and clearlylabelled with consecutive days from the start of therapy.

The present invention is illustrated but in no way limited by thefollowing examples:

EXAMPLE 1

The therapeutic system with daily dose of 1600 mg of amoxicillin and 125mg of clavulanic acid (1600/125) was provided by one conventional filmcoated tablet comprising 500 mg of amoxicillin in the form of trihydrateand 125 mg of clavulanic acid in the form of potassium clavulanate(Amoksiklav® 500/125) and two floating capsules each comprising of 550mg of amoxicillin in the form of trihydrate.

Composition of the Floating Capsule: Ingredients Weight Granulate:Amoxicillin trihydrate 481.76 mg Hydroxypropylmethylcellulose (HPMC,Methocel 36.32 mg K100LV) Microcrystalline cellulose(Avicel PH102) 36.32mg Mg stearate 5.60 mg Total weight of granulate 560.00 mg Tablet:Amoxicillin trihydrate 154.84 mg Hydroxypropylmethylcellulose (MethocelK100LV) 11.68 mg Microcrystalline cellulose(Avicel PH102) 11.68 mg Mgstearate 1.80 mg Total weight of tablet 180.00 mg Capsule: HPMC size 00Coating of capsule body: Surelease:HPMC E6 60:40 6.510 mg/cm² Capsulecap uncoatedMethod of Preparation:

Amoxicillin trihydrate, Methocel, Avicel and magnesium stearate werehomogeneously mixed to prepare the granulate.

Amoxicillin trihydrate, Methocel, Avicel and magnesium stearate werehomogeneously mixed and the resulting granulate was compressed intotablets each weighing 180 mg.

HPMC E6 was dissolved in water for 45 minutes and Surelease wassuspended in the HPMC solution with constant stirring for 10 minutes toobtain a 10% suspension. The suspension was sprayed over the HPMCcapsule bodies in a perforated coating pan at a temperature at about 40°C. to obtain the suitable amount of the coating.

The coated capsule bodies were filled with 560 mg of the granulate andthe tablet, and closed with the uncoated capsule cap.

EXAMPLE 2

The therapeutic system with daily dose of 2000 mg of amoxicillin and 125mg of clavulanic acid (2000/125) was provided by one film coated tabletAmoksiklav® 500/125 and three floating capsules each comprising 550 mgof amoxicillin in the form of trihydrate.

Composition of the Floating Capsule: Ingredients Weight Granulate:Amoxicillin trihydrate 448.0 mg Hydroxypropylmethylcellulose (MethocelK100LV) 53.2 mg Microcrystalline cellulose (Avicel PH102) 53.2 mg Mgstearate 5.6 mg Total weight of granulate 560.0 mg Tablet Amoxicillintrihydrate 144.0 mg Hydroxypropylmethylcellulose (Methocel K100LV) 17.1mg Microcrystalline cellulose (Avicel PH102) 17.1 mg Mg stearate 1.8 mgTotal weight of tablet 180.0 mg Capsule: HPMC size 00 Coating of capsulebody: Surelease:HPMC E6 60:40 6.510 mg/cm² Capsule cap uncoatedMethod of Preparation:

Amoxicillin trihydrate, Methocel, Avicel and magnesium stearate werehomogeneously mixed to prepare the granulate.

Amoxicillin trihydrate, Methocel, Avicel and magnesium stearate werehomogeneously mixed and the resulting granulate was compressed intotablets each weighing 180 mg.

HPMC E6 was dissolved in water for 45 minutes and Surelease wassuspended in the HPMC solution with constant stirring for 10 minutes toobtain a 10% suspension. The suspension was sprayed over the HPMCcapsule bodies in a perforated coating pan at a temperature at about 40°C. to obtain the suitable amount of the coating. The coated capsulebodies were filled with 560 mg of the granulate and the tablet, andclosed with the uncoated capsule cap.

EXAMPLE 3

A pharmacokinetic evaluation of the therapeutic system 1600/125 mg:

Twelve healthy male volunteers, aged 18-45 years, with body weight inthe range ±10% of ideal body weight were included in a crossover studywith a single dose administration of the drug in fed conditions. In oneperiod volunteers received one immediate-release Amoksiklav® tablet 500mg/125 mg and in the other period they received the therapeutic systemfor once-daily administration of 1600 mg/125 mg (1 tablet of Amoksiklav®500 mg/125 mg and 2 floating capsules each comprising 550 mg ofamoxicillin). There was a 7-day wash-out period between the two periods.Blood sampling time were the following: pre-dose, and 0.25, 0.5, 0.75,1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hafter dosing, that is, 22 samples per subject per period.

Amoxicillin and clavulanic acid concentrations were determined in theplasma. By comparing the plasma concentration profiles of amoxicillin ofboth medicaments, the contribution of the floating capsules in thetherapeutic system for once-daily administration was defined. The timeabove the MIC=1 μg/mL of amoxicillin and the time above the MIC=4 μg/mLof the treatment system for once-daily administration of amoxicillin andclavulanic acid of 1600 mg/125 mg were determined in the study.

Results of the Study:

The time above the MIC=1 μg/mL: 12.5 h and the time above the MIC=4μg/mL: 7.88 h, indicating 52.1% (for MIC=1 μg/mL) and 32.8% (for MIC=4μg/mL) of the 24-hour dosing interval. With respect to clavulanic acidboth medicaments are bioequivalent.

EXAMPLE 4

The therapeutic system with single dose of 1550 mg of amoxicillin and125 mg of clavulanic acid (1550/125) was provided by one conventionalfilm coated tablet comprising 1000 mg of amoxicillin in the form oftrihydrate and 125 mg of clavulanic acid in the form of potassiumclavulanate and one floating capsule comprising 550 mg of amoxicillin inthe form of trihydrate.

Composition of the Tablet 1000/125: Ingredients Weight Amoxicillintrihydrate 1164.14 mg  Potassium clavulanate 150.42 mg  Microcrystallinecellulose(Avicel PH102 dried) 119.04 mg  Polyplasdone XL dried 70.00 mgSodium lauryl sulfate 25.00 mg Cross-linked sodiumcarboxymethylcellulose 36.00 mg Colloidal silicon dioxide 12.00 mg Mgstearate 23.40 mg Hydroxypropylcellulose 22.12 mg Ethylcellulose  1.08mg Triethyl citrate  1.22 mg Talc  2.68 mg Titanium dioxide 11.70 mgPolisorbat 80  1.20 mg Total weight of tablet 1640.00 mg Method of Preparation:

Amoxicillin trihydrate, potassium clavulanate, microcrystallinecellulose, sodium lauryl sulphate, a part of polyplasdone XL,cross-linked sodium carboxymethylcellulose, colloidal silicon dioxide,and Mg stearate were mixed and slugged on rotary tabletting machines,then a part of a part of polyplasdone XL, cross-linked sodiumcarboxymethylcellulose, colloidal silicon dioxide, and Mg stearate wereadded, mixed and so prepared granulation was compressed into tabletseach weighing 1600 mg.

Ethanolic dispersion of hydroxypropylcellulose, ethylcellulose, triethylcitrate, talc, titanium dioxide and polisorbat was prepared usinglaboratory mixer and tablet cores were coated with the so prepareddispersion in a coating pan until 40 mg of coating was applied.

Composition of the Floating Capsule: Ingredients Weight Granulate:Amoxicillin trihydrate 487.95 mg Hydroxypropylmethylcellulose (HPMC,Methocel 36.32 mg K100LV) Microcrystalline cellulose(Avicel PH102) 30.13mg Sodium lauryl sulfate 25.00 mg Mg stearate 5.60 mg Total weight ofgranulate 585.00 mg Tablet: Amoxicillin trihydrate 154.84 mgHydroxypropylmethylcellulose (Methocel K100LV) 9.18 mg Microcrystallinecellulose(Avicel PH102) 9.18 mg Sodium lauryl sulfate 25.00 mg Mgstearate 1.80 mg Total weight of tablet 200.00 mg Capsule: HPMC size 00Precoated capsule: EC:HPC 40:60 3.267 mg/cm²Method of Preparation:

Amoxicillin trihydrate, Methocel, Avicel, sodium lauryl sulfate andmagnesium stearate were homogeneously mixed to prepare the granulate.

Amoxicillin trihydrate, Methocel, Avicel, sodium lauryl sulfate andmagnesium stearate were homogeneously mixed and the resulting granulatewas compressed into tablets each weighing 200 mg.

Ethanolic dispersion of hydroxypropylcellulose, ethylcellulose, triethylcitrate, and talc was prepared using laboratory mixer and preclosedcapsules were coated with the so prepared dispersion in a perforatedcoating pan at about 30° C. to obtain the suitable amount of thecoating.

The suspension was sprayed over the HPMC capsule bodies in a perforatedcoating pan at a temperature at about

The coated capsules were opened, filled with 560 mg of the granulate andthe tablet, and closed.

EXAMPLE 5

The therapeutic system with single dose of 1600 mg of amoxicillin and125 mg of clavulanic acid (1600/125) was provided by one film coatedtablet 1050/125 mg and one floating capsule comprising 550 mg ofamoxicillin in the form of trihydrate.

Composition of a Tablet 1050/125 mg: Ingredients Weight Amoxicillintrihydrate 1220.93 mg  Potassium clavulanate 150.60 mg  Silicifiedmicrocrystalline cellulose(Prosolv dried) 62.07 mg Polyplasdone XL dried70.00 mg Sodium lauryl sulfate 25.00 mg Cross-linked sodiumcarboxymethylcellulose 36.00 mg Colloidal silicon dioxide 12.00 mg Mgstearate 23.40 mg Hydroxypropylcellulose 22.12 mg Ethylcellulose  1.08mg Triethyl citrate  1.22 mg Talc  2.68 mg Titanium dioxide 11.70 mgPolisorbat 80  1.20 mg Total weight of tablet 1640.00 mg Method of Preparation:

Amoxicillin trihydrate, potassium clavulanate, silicifiedmicrocrystalline cellulose, sodium lauryl sulphate, a part ofpolyplasdone XL, cross-linked sodium carboxymethylcellulose, colloidalsilicon dioxide, and Mg stearate were mixed and slugged on rotarytabletting machines, then a part of a part of polyplasdone XL,cross-linked sodium carboxymethylcellulose, colloidal silicon dioxide,and Mg stearate were added, mixed and so prepared granulation wascompressed into tablets each weighing 1600 mg.

Ethanolic dispersion of hydroxypropylcellulose, ethylcellulose, triethylcitrate, talc, titanium dioxide and polisorbat was prepared usinglaboratory mixer and tablet cores were coated with the so prepareddispersion in a coating pan until 40 mg of coating was applied.

Composition of the Floating Capsule: Ingredients Weight Granulate:Amoxicillin trihydrate 487.95 mg Hydroxypropylmethylcellulose (HPMC,Methocel 36.32 mg K100LV) Microcrystalline cellulose(Avicel PH102) 30.13mg Sodium lauryl sulfate 25.00 mg Mg stearate 5.60 mg Total weight ofgranulate 585.00 mg Tablet: Amoxicillin trihydrate 154.84 mgHydroxypropylmethylcellulose (Methocel K100LV) 9.18 mg Microcrystallinecellulose(Avicel PH102) 9.18 mg Sodium lauryl sulfate 25.00 mg Mgstearate 1.80 mg Total weight of tablet 200.00 mg Capsule: HPMC size 00Precoated capsule: EC:HPC 40:60 3.267 mg/cm²Method of Preparation:

Amoxicillin trihydrate, Methocel, Avicel, sodium lauryl sulfate andmagnesium stearate were homogeneously mixed to prepare the granulate.

Amoxicillin trihydrate, Methocel, Avicel, sodium lauryl sulfate andmagnesium stearate were homogeneously mixed and the resulting granulatewas compressed into tablets each weighing 200 mg.

Ethanolic dispersion of hydroxypropylcellulose, ethylcellulose, triethylcitrate, and talc was prepared using laboratory mixer and preclosedcapsules were coated with the so prepared dispersion in a perforatedcoating pan at about 30° C. to obtain the suitable amount of thecoating.

The suspension was sprayed over the HPMC capsule bodies in a perforatedcoating pan at a temperature at about

The coated capsules were opened, filled with 560 mg of the granulate andthe tablet, and closed.

1. A therapeutic system for one or twice-daily administration ofamoxicillin and clavulanic acid comprising at least one immediaterelease amoxicillin/clavulanic acid pharmaceutical composition and atleast one gastroretentive pharmaceutical composition comprisingamoxicillin.
 2. The therapeutic system of claim 1, wherein amoxicillinis in the form of trihydrate.
 3. The therapeutic system of claim 1,wherein clavulanic acid is in the form of potassium clavulanate.
 4. Thetherapeutic system of claim 1, comprising from about 800 to 6000 mg ofamoxicillin and from 50 to 250 mg of clavulanic acid.
 5. The therapeuticsystem of claim 4, comprising about 1600 mg of amoxicillin and 125 mg ofclavulanic acid.
 6. The therapeutic system of claim 1, wherein the ratioof amoxicillin clavulanic acid is 3:1 to 35:1.
 7. The therapeutic systemof claim 6, wherein the ratio of amoxicillin to clavulanic acid is about12:1 to about 13:1.
 8. The therapeutic system of claim 1, wherein atleast one immediate release amoxicillin/clavulanic acid pharmaceuticalcompositions is selected from the group consisting of an immediaterelease tablet, film coated tablet, dispersible table, effervescenttablet, chewing tablet, capsule, pellets, granulate, and suspension.9-14. (canceled)
 15. The therapeutic system of claim 1, wherein at leastone gastroretentive pharmaceutical compositions is a floatingpharmaceutical composition.
 16. The therapeutic system of claims 15,wherein the floating pharmaceutical composition is in the form of afloating capsule. 17-18. (canceled)
 19. The therapeutic system of claim1, wherein at least one gastroretentive pharmaceutical compositioncomprises absorption enhancers of amoxicillin from the gastrointestinaltract. 20-25. (canceled)
 26. The floating capsule of claim 16, whereinthe capsule body is coated with poorly soluble coating.
 27. The floatingcapsule of claim 16, wherein the capsule body is coated with a coatingcomprising soluble and insoluble polymers.
 28. The floating capsule ofclaim 16, wherein the capsule body and the cap are coated with the samecoating.
 29. The floating capsule of claim 16, wherein the capsule bodyand the cap are coated with a different coating.
 30. The floatingcapsule of claim 16, wherein the capsule cap is uncoated.
 31. Thefloating capsule of claim 16, wherein the capsule body coating comprisesa combination of ethylcellulose and hydroxypropylmethylcellulose. 32.The floating capsule of claim 16, wherein the capsule body coatingcomprises acrylic and methacrylic acid copolymers.
 33. The floatingcapsule of claim 16, wherein the granulate comprises a release controlsubstance.
 34. The floating capsule of claims 33, wherein the granulatecomprises hydroxypropylmethylcellulose. 35-44. (canceled)